Is EXT2 p.Ala3Val (c.8C>T) pathogenic?

EXT2 p.Ala3Val (c.8C>T) is classified Likely benign in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1567); Rare (popmax 0.145%, eas); Associated with exostoses, multiple, type 2.

What condition is associated with EXT2 p.Ala3Val (c.8C>T)?

EXT2 p.Ala3Val (c.8C>T) is associated with exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Ala3Val (c.8C>T) in the general population?

EXT2 p.Ala3Val (c.8C>T) is rare (popmax 0.145%, eas) (gnomAD).

How is Multiple osteochondromas inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT2 p.Ala3Val (c.8C>T)?

AlphaMissense predicts likely benign (score 0.1567) — an in-silico prediction, not a clinical call.

EXT2 p.Ala3Val

c.8C>T · rs201185639 · VCV304571

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1567 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.145%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

exostoses, multiple, type 2

Computational evidence

Protein change
AlphaMissense	0.1567	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.145% East Asian · 65/44,880 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.106%

Overall 0.00558% 90/1,614,088 alleles · rare exomes 81/1,461,816 · genomes 9/152,272 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.145%	690
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00267%	37,509
Admixed American	0.00167%	60,022
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)	0.00102%	98,334

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EXT2
Protein: p.Ala3Val
Coding: c.8C>T
MANE Select: NM_207122
dbSNP: rs201185639
Type: single nucleotide variant
Location: chr11:44107720 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exostoses, multiple, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

Similar variants

EXT2 p.Ala3= Likely benign ★ same residue
EXT2 c.1079+1G>A Pathogenic ★★ same condition
EXT2 c.1079+1G>T Pathogenic ★★ same condition
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.1662+1G>C Likely pathogenic ★★ same condition
EXT2 c.536+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>C Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ext2-p-ala3val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown